RT Journal Article
SR Electronic
T1 Genomic MET amplification occurs early in NF1-related malignant peripheral nerve sheath tumor (MPNST) progression and is a potent therapeutic target
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 199000
DO 10.1101/199000
A1 Jacqueline D. Peacock
A1 Matthew G. Pridgeon
A1 Elizabeth A. Tovar
A1 Curt J. Essenburg
A1 Megan Bowman
A1 Zachary Madaj
A1 Julie Koeman
A1 Jamie Grit
A1 Rebecca D. Dodd
A1 Diana M. Cardona
A1 Mark Chen
A1 David G. Kirsch
A1 Flavio Maina
A1 Rosanna Dono
A1 Mary E. Winn
A1 Carrie R. Graveel
A1 Matthew R. Steensma
YR 2017
UL http://biorxiv.org/content/early/2017/10/05/199000.abstract
AB Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with concomitant amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and NF1 ablation (NF1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1-MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPSNTs with MPNSTs derived from NF1KO/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and NF1KO/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. To investigate the therapeutic potential of MET inhibition among tumorgrafts derived from the respective MPNST models, we tested the highly selective MET inhibitor, capmatinib. NF1-MET MPNSTs were uniformly sensitive to MET inhibition whereas only a small subset of NF1-P53 and NF1 MPNSTs were inhibited. These results confirm that MET activation is sufficient for Schwann cell dedifferentiation into MPNSTs in the context of NF1 deficiency. RAS-MET signal interactions may be an important driver of MPSNT disease progression.